P674: UPDATED RESULTS OF A PHASE 1B STUDY OF IBRUTINIB (IBR) PLUS OBINUTUZUMAB (OBIN) IN PATIENTS WITH RELAPSED OR REFRACTORY (R/R) CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
Authors: C. Ryan, D. Brander, P. Barr, S. Tyekucheva, Y. Ren, L. Hackett, M. McDonough, K. Pena Del Aguila, M. McEwan, M. Collins, J. Abramson, E. Jacobsen, A. LaCasce, D. Fisher, J. Brown, M. Davids
Journal: HemaSphere (2022)

Background: Combination ibr + obin was approved in frontline CLL based on results of iLLUMINATE; however, less data are available on this regimen in R/R CLL. Though active in R/R CLL, ibr monotherapy in RESONATE led to 4-year (yr) PFS/OS of ~45%/65%, leaving room for improvement. We previously reported initial safety and efficacy results of this phase 1b study investigating ibr + obin in R/R CLL (Davids et al., EHA 2020). Here, we report updated results, with median follow-up now of 41.5 months (mos). Aims: To assess longer-term safety and efficacy of ibr + obin in patients (pts) with R/R CLL. Methods: We conducted a phase 1b, investigator-initiated study of ibr + obin in R/R CLL (NCT02537613). The primary objective was to assess safety of 3 different drug sequencing regimens in cycle 1; the main secondary objective was to assess efficacy. Pts were randomized 1:1:1 to either receive obin 1 mo before ibr, ibr 1 mo before obin, or start concomitantly. Both drugs were given at the approved doses and schedule, with 6 total cycles of combination followed by ibr monotherapy until progression or unacceptable toxicity. Notable eligibility criteria: requiring treatment (tx) for R/R CLL/SLL by 2008 iwCLL criteria, ECOG PS ≤2, no prior ibr or obin. Assessments: toxicities by CTCAE v4, efficacy by 2008 iwCLL criteria, MRD by 4-8 color flow (10-4 sensitivity). Serum concentrations of 21 cytokines were assessed pre-tx and after 1 week of combination tx in a representative subset of 27 pts (n=9 per arm) by bead-based multiplex immunoassay (Eve Technologies, Calgary). Results: 52 pts were accrued, and all received ≥1 cycle of combination tx. Median age: 67 yrs (range 33-84); 77% male; median # prior tx: 1 (range 1-6); 25% del(17p) or TP53 mut; 27% del(11q); 50% unmutated IGHV; 27% bulky LAD (nodes ≥5 cm). As of 14 Feb 2022: median follow-up 41.5 mos (range 2.3-73.3). 27 pts (52%) remain on tx. All-grade heme toxicities: thrombocytopenia (88%; 23% Gr3/4), neutropenia (71%; 37% Gr3/4), febrile neutropenia (8%, all Gr3/4), anemia (73%; 8% Gr3). Notable non-heme toxicities: bruising (58%, all Gr1/2), arthralgia (38%, all Gr1/2), diarrhea (37%, all Gr1/2), transaminitis (35%; 4% Gr3), ≥Gr3 infection (17%, all Gr3), and cardiotoxicities: hypertension (46%; 10% Gr3), atrial fibrillation (21%; 10% Gr3). 1 pt had sudden cardiac death after 11 mos on study. 7 pts required ibr dose-reduction due to toxicity. The best ORR is 96%, including 50% CR and 46% PR (Fig. 1A). All 3 pts who previously progressed on venetoclax responded (1 CR, 2 PR). By ITT, 10/52 (19%) achieved a best response of undetectable MRD in bone marrow (BM, 44 pts tested), and 14/52 (27%) in peripheral blood (PB, 34 pts tested). 4-yr PFS and OS are 74% and 93% (Fig. 1B-C), with 3 deaths (n=1 each: sudden death, MDS, Richter’s syndrome). Pts who achieved BM and PB undetectable MRD had a significantly larger decrease in circulating CCL4 (p=0.02) and CXCL13 levels (p=0.01), respectively, comparing baseline to 1 week of combination tx (Fig. 1D). Image:Summary/Conclusion: Ibr + obin is a highly active combination in R/R CLL, achieving 50% CR and 4-yr PFS/OS of 74%/93%, suggesting a potential positive impact of obin (though possibly also reflecting an earlier relapse population than RESONATE). Responses were observed in all 3 pts who had progressed after venetoclax, including 1 CR. With ~3.5 yrs median follow-up, and some pts on tx over 6 yrs, cardiotoxicity was consistent with prior ibr studies, and no new safety concerns have emerged. Our data support continued exploration of combination BTK inhibitor plus obin in R/R CLL.